Project Summary/Abstract Inherited retinal degenerative diseases affect approximately 3.5 million people worldwide. Retinitis Pigmentosa (RP) causes progressive degeneration of rod and cone photoreceptor cells, resulting in the complete loss of vision. Nevertheless, surviving retinal neurons downstream of photoreceptor cells provide an exciting entry point for therapy. Several approaches including the use of microbial opsins and implanted electrode arrays within these downstream cell types have restored useful features of vision, however, low light-sensitivity, invasiveness, and poor resolution, describe some of the challenges of these methods. The research proposed here, seeks to dramatically advance vision restoration using a novel optogenetic approach based on native retinal receptors that support vision of natural scenes at natural intensities, without the need for an exogenously applied photoswitch. This will be done using a combination of experimental techniques including molecular biology, AAV-mediated gene transfer, multielectrode array recordings, two-electrode voltage-clamp electrophysiology, and visually-guided behavioral assays. Several native retinal light sensors, rhodopsin and melanopsin, have been ectopically expressed by our lab and others in remaining retinal cells of a mouse model of human RP. While these studies elegantly demonstrate the efficacy of converting retinal cells lacking intrinsic photosensitivity into functional pseudo-photoreceptor cells with high light sensitivity, and capable of restoring basic features of vision, both receptors suffer from kinetics too slow to support vision in motion. The research plan describes a method to uniquely combine both sensitivity comparable to that of rhodopsin, together with speed, in neurons of the inner retina that survive for decades following photoreceptor cell loss. This effort will provide crucial insight on the most essential components required for meaningful, complex visual restoration and a potential foundation for future treatments of inherited retinal degenerative diseases.